Factor Xa is the penultimate enzyme in the coagulation cascade. Inhibition of Factor Xa may be achieved, for example, by direct complex formation between a suitable inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III. Effective factor Xa inhibition may be achieved by administering compounds by oral administration, continuous intravenous infusion, bolus intravenous administration or any other suitable route such that it preferably achieves the desired effect of preventing the Factor Xa induced formation of thrombin from prothrombin.
Anticoagulant therapy is often indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels include, for example, acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting of the coronary (CABG) or peripheral arteries.
Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (i.e., restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, or DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition may be characterized by a rapid consumption of coagulation factors and their plasma inhibitors which may result in the formation of life-threatening clots throughout the microvasculature of several organ systems. The indications discussed above include some, but not all, of the possible clinical situations where anticoagulant therapy may be warranted. Those experienced in this field are well aware of the circumstances requiring either acute or chronic prophylactic anticoagulant therapy.
Both free Factor Xa and Factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) may be inhibited by N-[(aminomethyl) phenyl]propyl amide compounds. A particularly promising N-[(aminomethyl) phenyl]propyl amide compound is methyl (2R,3R)-2-{3-[amino(imino)methyl]benzyl}-3-{[4-(1-oxido-4-pyridinyl)benzoyl]amino}butanoate, i.e., the compound of formula (I) (hereinafter referred to as “Compound (I)”):
N-[(aminomethyl) phenyl]propyl amide compounds, including Compound (I), are disclosed in commonly assigned U.S. Pat. No. 6,080,767, which is based on an application that claims priority benefit under 35 U.S.C. § 371 of International application Serial No. PCT/US96/20770 (designating the United States) filed Dec. 23, 1996, which, in turn, claims priority benefit of U.S. Provisional application Ser. No. 60/009,485 filed Jan. 2, 1996.
Treatment and/or prevention of the foregoing pathological conditions may be accomplished by administering a therapeutically effective amount of Compound (I) to a patient in need of such treatment and/or prevention. Treatment with such forms of Compound (I) may be accomplished by its use alone, as an ingredient of a pharmaceutical composition, or in combination with one or more other medications. Compound (I) may be administered enterally or parenterally in solid or liquid dosage forms.
Crystalline forms of Compound (I) have not been known to exist previously. There exists a need for crystalline forms which may exhibit desirable and beneficial chemical and physical properties. There also exists a need for reliable and reproducible methods for the manufacture, purification, and formulation of Compound (I) to permit its feasible commercialization. The present invention is directed to these, as well as other important ends.